The overall goal of the research program is to understand the mechanism(s) of end-organ damage,[unreadable] particularly end-stage renal disease (ESRD). This research problem is relevant to the clinical problem[unreadable] of the increased incidence of target organ damage associated with hypertension. Although the rate of[unreadable] stroke and heart disease has gradually declined over the last several decades, the rate of ESRD has[unreadable] been steadily increasing. The African American population particularly experiences a[unreadable] disproportionately greater risk for ESRD. We hypothesize that one possible mechanism of ESRD[unreadable] associated with hypertension may be stressed-induced renal ischemia in the presence of impaired NO[unreadable] bioavailability. In support of this goal, preliminary data generated in the applicant's laboratory[unreadable] demonstrate that the physiologic stress of infrequent bouts of exhaustive exercise cause progressive[unreadable] gross histologic renal damage in the moderately hypertensive endothelial NO synthase (eNOS)[unreadable] knockout mouse, but not in the wild type control. It is proposed that physiologic stress such as[unreadable] infrequent exhaustive exercise results in increased renal vasoconstrictor activity and ischemia which in[unreadable] turn lead to increased production of reactive oxygen species and cytokine production in the face of an[unreadable] NO deficiency. Therefore, in an effort to generate preliminary data to support this hypothesis we[unreadable] propose the following Specific Aims. Specific Aim 1 is designed to generate renal vasoconstriction[unreadable] data. Mice will be chronically implanted with both renal blood flow (RBF) and blood pressure probes to[unreadable] measure RBF and blood pressure at rest and during physiologic stress of infrequent running to[unreadable] exhaustion in control and eNOS knockout mice. Renal vascular resistance will be calculated from these[unreadable] values. It is expected that eNOS knockout mice will have a greater and more sustained renal[unreadable] vasoconstriction with subsequent ischemia as compared to normal wild type mice. Specific Aim 2 is[unreadable] designed to generate data showing that ischemia develops in the kidney during the stress of infrequent[unreadable] running to exhaustion. Plasma, urine as well as tissue will be collected for measurement of markers of[unreadable] vascular ischemia. Since it is not certain which markers are best to specifically detect renal ischemia[unreadable] we will measure various vascular ischemia markers in plasma, urine and renal tissue.